Mutations in Krüppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression

Viprakasit, Vip; Ekwattanakit, Supachai; Riolueang, Suchada; Chalaow, Nipon; Fisher, Chris; Lower, Karen M.; Kanno, Hitoshi; Tachavanich, Kalaya; Bejrachandra, Sasithorn; Saipin, Jariya; Juntharaniyom, Monthana; Sanpakit, Kleebsabai; Tanphaichitr, Voravarn S.; Songdej, Duantida; Babbs, Christian; Gibbons, Richard J.; Philipsen, Sjaak; Higgs, Douglas R.

doi:10.1182/blood-2013-09-526087

Cited by 77 publications

(107 citation statements)

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“…KLF1 mutations can lead to loss or gain-of-function, giving rise to distinct phenotypic states, including CDA IV, CNSHA, and mild anemia, and induce increases in HbF level. [12][13][14] In contrast, the patients in this study exhibited the thalassemia phenotypes and unusual changes associated with KLF1 loss-of-function mutations. For instance, the microcytic hypochromic anemia with poikiloblast and abnormal heterochromatin organization in erythroblasts are not observed in CDA IV.…”

Section: Discussioncontrasting

confidence: 58%

“…In that study, most of the cases had co-inherited α or β thalassemia mutations and it was therefore not possible to clearly discern their hematological status. 14 Studies suggest that the amount and type of mutant KLF1 protein produced are responsible for different RBC phenotypes. [15][16][17][18] Further research is required to determine the relationship between the various KLF1 mutations and the severity of clinical phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

et al. 2015

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Krüppel-like factor 1 (KLF1) regulates erythroid lineage commitment, globin switching, and the terminal maturation of red blood cells. Variants in human KLF1 have been identified as an important causative factor in a wide spectrum of phenotypes. This study investigated two unrelated male children in China who had refractory anemia associated with poikilocythemia. These were accompanied by an upregulation of biochemical markers of hemolysis, along with abnormal hemoglobin (Hb) level and elevated reticulocyte counts. Next-generation sequencing revealed that the patients were compound heterozygotes for a KLF1 frameshift mutation c.525_526insCGGCGCC (p.(Gly176ArgfsTer179)) and one of two missense variants, c.892 G4C (p. (Ala298Pro)) and c.1012C4T (p.(Pro338Ser)). The subjects had microcytic hypochromic anemia, and their healthy parents had single mutation. The two missense mutations affected a highly conserved codon in the zinc finger DNA-binding domain of KLF1, but the protein stability was unaffected in K-562 cells. A KLF1-targeted promoter-reporter assay showed that the two mutations reduce the expression of the HBB, BCL11A, and CD44 genes involved in erythropoiesis, with consequent dyserythropoiesis and an α/non-α chain imbalance. A systematic analysis was performed of the phenotypes associated with the KLF1 mutations in the two families, and the clinical characteristics and differential diagnoses of the disease are presented. This is the first report of an autosomal recessive anemia presenting with microcytic hypochromia, abnormal Hb profile, and other distinctive erythrocyte phenotypes, and provides insight into the multiple roles of KLF1 during erythropoiesis.

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Section: Discussioncontrasting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

et al. 2015

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“…Sequencing of genomic DNA and complementary DNA (cDNA) confirmed the insertion was absent from cDNA rendering the patient functionally homozygous for the 2015C>T exon 14 mutation and therefore clinically affected (Fig S3). P38, referred with unclassified CDA, had compound heterozygosity for two pathogenic KLF1 mutations previously reported in CDA‐IV, although not previously documented in the same patient (Gallienne et al , 2012; Viprakasit et al , 2014). The clinical features, early‐onset transfusion‐dependent, microcytic anaemia with reticulocytosis, jaundice, hepatosplenomegaly, high HbF (14·2%) and bone marrow erythroid hyperplasia with binucleate erythroblasts and chromatin bridges, were also consistent with CDA‐IV.…”

Section: Resultsmentioning

confidence: 80%

A novel 33‐Gene targeted resequencing panel provides accurate, clinical‐grade diagnosis and improves patient management for rare inherited anaemias

et al. 2016

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SummaryAccurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next‐generation‐sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical‐grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically‐reliable diagnostic test and minimize false‐negative results we developed an open‐source tool (CoverMi) to accurately determine base‐coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33‐gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS‐based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.

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“…However, some mutations lead to anemias (Arnaud et al, 2010;Huang et al, 2015;Jaffray et al, 2013;Singleton et al, 2011;Viprakasit et al, 2014; reviewed by Perkins et al, 2016). The human KLF1 mutation (E325K) in congenital dyserythropoietic anemia (CDA) (Arnaud et al, 2010;Jaffray et al, 2013;Singleton et al, 2011) is at the same amino acid as that seen in the mouse Nan mutant (Heruth et al, 2010;Siatecka et al, 2010b), albeit a different substitution.…”

Section: Introductionmentioning

confidence: 99%

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

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et al. 2017

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Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/ KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.

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Mutations in Krüppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression

Abstract: Key Points KLF1 mutations cause severe congenital hemolytic anemia associated with a deficiency of red cell pyruvate kinase. A severe KLF1 deficiency causes hereditary persistence of embryonic globin synthesis.

Cited by 77 publications

References 41 publications

Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

A novel 33‐Gene targeted resequencing panel provides accurate, clinical‐grade diagnosis and improves patient management for rare inherited anaemias

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

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